Biopharmaceutics 4.0, Advanced Pre-Clinical Development of mRNA-Encoded Monoclonal Antibodies to Immunosuppressed Murine Models

Abstract

Administration of mRNA against SARS-CoV-2 has demonstrated sufficient efficacy, tolerability and clinical potential to disrupt the vaccination field. A multiple-arm, cohort randomized, mixed blind, placebo-controlled study was designed to investigate the in vivo expression of mRNA antibodies to immunosuppressed murine models to conduct efficacy, safety and bioavailability evaluation. Enabling 4.0 tools we reduced animal sacrifice, while interventions were designed compliant to HARRP and SPIRIT engagement: (a) Randomization, blinding; (b) pharmaceutical grade formulation, monitoring; (c) biochemical and histological analysis; and (d) theoretic, statistical analysis. Risk assessment molded the study orientations, according to the ARRIVE guidelines. The primary target of this protocol is the validation of the research hypothesis that autologous translation of Trastuzumab by in vitro transcribed mRNA-encoded antibodies to immunosuppressed animal models, is non-inferior to classical treatments. The secondary target is the comparative pharmacokinetic assessment of the novel scheme, between immunodeficient and healthy subjects. Herein, the debut clinical protocol, investigating the pharmacokinetic/pharmacodynamic impact of mRNA vaccination to immunodeficient organisms. Our design, contributes novel methodology to guide the preclinical development of RNA antibody modalities by resolving efficacy, tolerability and dose regime adjustment for special populations that are incapable of humoral defense.

Pharma 4.0 Continuous mRNA Drug Products Manufacturing

“…mRNA drug products have demonstrated safe administration and efficacy, thus offering a needed promising vaccination alternative due to their potency, adaptive pre-clinical to bedside trial design, and rapid and low-cost development and manufacturing [ 65 ]. Functional immunity by formulated mRNA has been elicited in vivo against several infectious diseases such as Zika virus, influenza virus, rabies virus, and others, by utilizing various sequence-optimized mRNA constructs encapsulated into LNP carriers [ 66 ].…”

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

“…Furthermore, as mRNA technology matures, its convergence with emerging adoptive immunotherapies can materialize into safer and more effective approaches such as the development of state-of-the-art chimeric antigen receptor T-cells ( Figure 1 ). The resulting cellular therapeutic product has several advantages compared to the one derived by a more classical approach, due to the transient nature of mRNA expression and non-integration of the foreign material to the cell’s genome: minimized cytotoxicity resulting from on-target off-tumor effects, easier production under good manufacturing practices favorable clinical validation and regulatory treatment [ 4 , 5 , 6 , 7 , 8 ].…”